Mitochondrial encephalomyopathies are important causes of mental retardation. The investigators are focusing on disorders associated with mitochondrial DNA (mtDNA) point mutations, especially mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). In his project, Dr. D. C. De Vivo, P.I., will continue to characterize the natural history of MELAS, correlating cognitive and behavioral deficits in probands and oligosymptomatic relatives with cerebral energy metabolism assessed by MRI and MRSI. He will also continue a clinical trial with dichloroacetate (DCA) to be completed in 2006. This is a placebo-controlled, randomized, blinded three-year study of a large cohort of MELAS patients. In this unique patient population, Dr. De Vivo will study early biomarkers of brain dysfunction using brain imaging techniques (PET, fMRI). In his project,: Dr. E. A. Schon, P.I., will concentrate on pharmacological approaches to mtDNA-related disorders aimed at "downshifting" the percentage of mutant mtDNAs. His findings that ketone bodies act as selection agents for wild-type function in cultured cybrid cells heteroplasmic for the T8993G NARP mutation will be extended to cybrid cell lines harboring other mutations, including the A3243G MELAS mutation. To approximate clinical conditions, he will ask whether the downshifting effect of ketone bodies persists in the presence of other substrates, and whether it occurs in terminally differentiated cells, such as myotubes. In his project, Dr. M. Davidson, P.I., will generate an in vitro model of the blood-brain barrier (BBB) to confirm preliminary neuropathological data (Project by Bonilla) suggesting a breakdown of BBB function in MELAS. The model is based on co-cultures of human astrocytes and endothelial cells, both normal and homoplasmic for the A3243G MELAS mutation. In his project, Dr. E. Bonilla, P.I., will extend preliminary studies on two brain structures: the choroids plexus and the ependyma, involved in the BBB and in cerebrospinal fluid (CSF) homeostasis. He will determine the distribution of the lactate and water transporters and of tight junction proteins in the BBB of normal and MELAS brains using immunohistochemistry and immunoblotting. To correlate neuropsychological findings in MELAS patients (Project by Devine) with neuropathology, he will conduct immunohistological and molecular studies of respiratory chain components and of calcium-binding proteins in the hippocampus of patients with MELAS. The Core Unit (Dr. S. DiMauro, Director; Dr. E. A. Schon, Co-Director) will provide direction, administration, external consultation, and shared equipment/technical service to the program as a whole.